Tulearin C is at first sight a rather simple polyketide natural product. Only seven stereocenters of which only four are contiguous and none of them is quaternary. Nevertheless no useful route to this compound has been established to date despite some potential antiproliferative action against human leukaemia cell lines.

The group around Fürstner built their synthesis upon a RCAM (ring-closing alkyne metathesis) with subsequent trans-selective hydrosilylation/protodesilylation to get the trans alkene. This critical feature was the major problem of earlier approaches which relied on a trans selective RCM which instead gave a mixture of trans and cis alkenes of virtually 2 : 1.

Scheme 1

Breaking down the molecule into two halves the group reduced the problem to the common starting unit 1. This glutarate monoester is available in large quantities from dimethyl-3-methylglutarate.

Desymmetrizing saponification of one of the ester groups with a pig liver esterase (PLE) and further enhancing ee by crystallization of the crude acid with cinchonidine gave ester 1. You should have a look in the SI how they did this interesting saponification. After formation of the lithium salt the ester was reduced to the alcohol and cyclized to give lactone 2. Wittig reaction then furnished dichloride 3 which was reacted with excess methyl lithium to give alcohol 4 and after DMP oxidation aldehyde 5.

The key transformation of this scheme is detailed at the end.

Scheme 2

Aldehyde 5 then underwent stereoselective alkynylation under Carreira’s conditions to give diyne 6. Regioselective reduction of the internal alkyne and quench with iodine was followed by silylation of the free alcohol. The excellent regiocontrol can be ascribed to the alcohol function which guides the Red-Al to the correct end of the triple bond. Palladium catalyzed methylation and subsequent desilylation then furnished the green fragment. Direct introduction of the methyl group in the hydrometallation step with Red-Al did not produce any product at all.

Scheme 3

As mentioned above the synthesis of the second fragment commenced with key intermediate 2. Claisen reaction with ethyl acetate and reduction of the resulting dicarbonyl compound gave diol 9. Protection of the primary alcohol was necessary to get the following methylation done. MOM-protection of the secondary alcohol produced ester 10. After desilylation of the TBDPS group an Appel reaction of the free alcohol furnished iodide 11

Scheme 4

The second half of the red fragment was synthesized from butynol. Hydrozirconation with Schwartz’ reagent in the presence of DiBAl-H and iodine quench was followed by triflation and alkynylation to get iodide 12.

Scheme 5

Both parts were combined by first generating the alkylzinc species from 11 which underwent a Negishi coupling with iodide 12. Sharpless dihydroxylation and subsequent MOM cleavage was followed by global TBS protection and saponification of the ester grouping.

Scheme 6

Esterification of 15 with 8 was accomplished with EDC in almost quantitative yield. RCAM with catalyst C was done in toluene in excellent yield although some heating was necessary. Trans-selective hydrosilylation gave lactone 17 from which the siloxy group was removed with AgF. TBS removal under standard conditions then produced Tulearin C.

Scheme 7

And here are the details concerning the formation of key fragment 4. It is some kind of Grob fragmentation and I would compare it to the well known Eschenmoser fragmentation. Two possible reaction pathways are shown in the paper of which the left one is preferred.

As can easily be seen from the scheme the first step is a metal-halogen exchange to give a carbenoid-like carbon atom. The next step might on the one hand be an intramolecular E2-reaction to give the acetylenic chloride which undergoes another metal-halogen exchange and subsequent alkylation with in situ formed MeCl (blue arrows).

Or alternatively the vinyl-lithium species is alkylated with in situ formed MeCl before the second chloride atom undergoes a metal-halogen exchange and further fragmentation (green arrows).

Independent of the intermediates the same product is formed in good yield. In the original paper some applications of this transformation are shown and a detailed investigation of the mechanism and further application are underway. Also two examples are shown in which allenes instead of alkynes are formed.